FR2520741A1 - NOVEL BENZOTHIOPHENE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS - Google Patents

Abstract

THE INVENTION CONCERNS (N-ALKYL-N-ALLYLAMINO-ALKYL) BENZOTHIOPHENES IN WHICH THE ALLYLAMINO-ALKYL SIDE CHAIN IS LOCATED IN POSITION 2, 3, 4, 5, 6 OR 7 OF THE BENZOTHIOPHENIC CYCLE, THE COMPONENT LATERAL CHAIN TERTIO-ALKYL-ETHYNYL OR ALCENYL-ETHYNYL AS A TERMINAL GROUP WHEN SITUATED IN POSITION 2 OR 3. THESE COMPOUNDS CAN BE USED AS CHEMOTHERAPEUTIC AGENTS, IN PARTICULAR AS ANTI-MYCOTIC AGENTS.

Description

The object of the present invention is to

  calves derived from benzothiophene, their preparation and

  their use as medicines.

  The invention relates to (N-alkyl-N-allylamino-alkyl) benzothiophenes in which the allylamino-alkyl side chain

  is in position 2, 3, 4, 5, 6 or 7 of the benzothiophenic

  that the side chain containing a tert-alkyl-ethynyl or alkenyl-ethynyl group as the terminal group when it is located

in position 2 or 3.

  More particularly, the invention relates to compounds of the formula

C N CH 2 CH = CH C C R (1)

  wherein R 1 is hydrogen or methyl, R 2 is methyl or ethyl, R 3 is tertiary alkyl or alkenyl, and R 4 and R 5 are each independently one of other, hydrogen, halogen, hydroxy, lower alkynyl, cyano, formyl, lower alkoxy,

  lower alkylcarbonyl, lower alkoxycarbonyl, a group

  lower alkyl optionally bearing one or more substituents selected from halogen and cyano, hydroxy, lower alkylthio and lower alkoxy,

  or a lower alkenyl group carrying one or more

  substituents selected from halogens and cyano group,

  in free base form or in the form of an acid addition salt.

  European Patent Application No. 1,024,587 describes a large number of aromatic allylamines without specifically describing compounds of the type included in the present invention. The Applicant has now found that in the tests as described below,

  the compounds of the present invention exert not only

  There is also a high activity against dermatophytes, but also surprisingly high activity against candida spp that the compounds of the aforementioned European patent application do not possess to the same degree. According to the process of the invention, to prepare the compounds of formula I a) a compound of formula II is reacted

R, R 1, R 2 (II)

CH N Ht

  in which R 1, R 2, R 4 and R 5 have the significances

  previously given with a compound of formula III

A-CH 2 -CH = CH-C- = C-R 3 (III)

  in which R 3 has the meaning given above.

  and A means a group capable of being removed, or b) reacting a compound of formula IV R 4 f j

R 4 CH A

  Iv) in which RV, R 4 and R 5 have the meanings

  data previously and A means a group sus-

  can be removed with a compound of formula V

, 2 (V)

HN CH 2 CH = CH C C R 3

  in which R and R have the meanings already given,

2 R 3

  and recovering the compounds thus obtained in the form

  free base or as an acid addition salt.

The other compounds of

  the invention can be prepared analogously.

  Processes a) and b) can be carried out according to known methods, for example in a solvent which is inert under the conditions of the reaction, such as

  lower alcohol, such as ethanol, possibly

  mix with water, an aromatic hydrocarbon such as, for example, benzene or toluene, a cyclic ether such as dioxane, or a dialkylamide.

  a carboxylic acid such as dimethylformamide.

  One operates at a temperature between the temperature

  room temperature and the reflux temperature of the mixture

  reaction, preferably at room temperature.

  The group A that can be eliminated can be, for example, a halogen, for example chlorine or bromine, or an organic sulfonyloxy group containing

  1 to 10 carbon atoms, for example an alkyl group

  arylsulfonyloxy such as the tosyloxy group, or a

  alkylsulfonyloxy group such as the mesyloxy group.

  When appropriate, the reaction is advantageously carried out in the presence of an acid-accepting agent.

  such as an aluminum hydroxide or carbonate of

  calin or alkaline earth, such as carbonate of

sodium or potassium.

  The compounds of formula I can be converted according to known methods into their salts

addition of acids and vice versa.

  The compounds of formula I and their intermediates

  can be obtained in the form of a

  ge of the different cis / trans isomers that can be

  separated according to known methods.

  When a substituent means an alkyl group or contains an alkyl group, the alkyl group in question may be straight-chain or branched and preferably contains 1 to 4 carbon atoms, especially 1 or 2 carbon atoms.

  alkenyl or alkynyl may be linear or branched

  and preferably contain from 2 to 6 carbon atoms, especially from 2 to 4 carbon atoms, as substituents of the ring system or 3 or 4 (alkenyl) carbon atoms as substituent R 3 to, for example, a vinyl or ethynyl group as a substituent of the system

  cyclic and allyl, preferably 5-allyl, as

  R 3 When R 3 is a tertiary alkyl group,

  Preferably, it contains from 4 to 10 carbon atoms, especially from 4 to 6 carbon atoms, and may be, for example, tert-butyl, preferably halogen, fluorine, chlorine or bromine, preferably

chlorine or bromine.

  The starting materials of formula II are in part new and can; be prepared according to the

  known methods, for example by reacting a

laid down of formula VI

R 4 R

  Where R 1, R 4 and R are as previously defined and Hal is halogen, with a compound of formula VII

R 2 -NH 2 (VII)

  in which R 2 has the meaning given above. This process can be carried out

  analogous to processes a) and b) described above.

  The starting products of formulas III and V are partially new and can be prepared according to the known methods, for example according to the following reaction scheme

HC C R 3

Bu Li / Hexane Me "C C R 3

+ OHC CH = CH 2

H 2 C = Cl-CH-C = C-R 3

OH HA A-CH 2 -CH = CH-C = CR 3

R 2 + R 2 NH 2

HN-CH 2 -CH = CH-C; C R 3

  In this reaction scheme, R 2, R 3 and A have the meanings given above and Me d) means

the cation of a metal.

  The reaction conditions are those customarily used in such reactions, the various intermediate products being able, where appropriate, to be reacted subsequently without prior isolation.

  isolate the compounds according to known methods.

  Other starting materials and intermediates are known or can be prepared

according to known methods.

  The compounds of formula I possess

  These chemotherapeutic properties can therefore be used as medicaments. In particular, the compounds of formula I exert an antimycotic action as is apparent from in vitro tests on families and various types of fungi, including Trichophyton spp., Aspergillus spp., Microsporum spp., Sporotrix.

  schenkii and especially Candida spp, at concentrations

  for example between 0.1 and 25 μg / ml.

  The antimycotic activity exerted by the compounds of formula I has also been demonstrated in vivo in the experimental model of dermal mycosis.

  in the guinea pig 24 hours after infection, it is recommended that

  daily nister substance to try on animals

  for 7 days, or by local application in cash

  the test substance being mixed with polyethylene glycol, either orally or subcutaneously, the substance to be tested

  try being in the form of a suspension.

  The activity against Candida has been demonstrated in vivo using conventional experimental models, such as the disseminated infection or infection model.

  intravaginal / intrauterine in mice or rats.

  A clear antimycotic activity is observed when the compounds of formula I are applied topically to a concentration of, for example, between 0.01 and 0.5%. Oral activity was observed in vivo on guinea pig trichophytosis at doses by

example between 2 and 70 mg / kg.

  Thanks to these properties, the compounds of formula I can be used therapeutically as chemotherapeutic agents, in particular as antimycotic agents. A suitable daily dose will be between about 70 and 2000 mg of the compound of formula I which will be administered, for example, in the form of unit doses each containing between about 17, 5 and 1000 mg of active substance two to four times per

  day or in delayed release form.

  The active ingredient can also be administered by the route.

topical.

  The compounds can be used in the free base state or in the form of a chemically acceptable acid addition salt. Such salts have the same degree of activity as the free bases. hydrochloride, hydrogen fumarate or naphthalene-1,5-disulfonate. The invention therefore relates to the compounds of formula I, in free base form or in the form of an acid addition salt acceptable from the point of view

  chemotherapy, for use as a medicinal

  particularly as chemotherapeutic agents

  The invention also relates to a medicament containing, as active ingredient, a compound of formula I in free base form or in the form of an acid addition salt.

  chemotherapeutically acceptable.

  For their therapeutic use, the compounds of the invention may be admixed with chemotherapeutically acceptable diluents and carriers and, optionally, other excipients. They may be administered orally in the form of tablets or capsules. The compounds may also be applied topically, for example in the form of ointments or creams,

  or parenterally or intravenously.

  of the active substance depends on the compound used, the desired treatment, the type of formulation, etc.

  general, satisfactory results are obtained when

  that formulations intended for topical application

  contain the active ingredient at a concentration of

  for example between 0.05 and 5% by weight, in particular

  between 0.1 and 1% by weight of such compositions.

  also part of the invention.

  The preferred meanings of the substituents present in the compounds of formula I are as follows: R 1 signifies hydrogen R 2 signifies a methyl group R 3 signifies a) a C 4 -C 10 alkyl group b) a C 4 alkyl group -C 6 c) tert-butyl, tert-pentyl, especially t-butyl d) C 3 -C 6 alkenyl

(e) an allyl group, specially

  6-allyl R 4, R 5 are hydrogen or a) C 1 -C 4 alkyl b) C 1 -C 2 alkyl, especially methyl c) halogen, especially chlorine d) C 1 -C 4 haloalkyl group, especially CF 3 e) an alkylcarbonyl group whose alkyl residue is C 2 -C 5, especially acetyl; f) a C 1 -C 4 hydroxyalkyl group, especially -CH 2 H g) a cyano group h) an alkylthio or alkoxy group

at C 1 -C 4, for example methyl

  thio or methoxy i) a formyl group j) alkenyl C 2 -C 4 (for example vinyl) optionally substituted with halogen k) C 2 -C 4 alkynyl, for example ethynyl one of the substituents R 4 and R 5 preferably means hydrogen.

  The allylamino side chain is preferably

  fixed on the benzene ring especially in

  position 4 or 7, more preferably in position 7.

  The substituents R 4 and / or R 5 are preferably on the

  thienyl ring, that is to say in position 2 and / or 3.

  The preferred compounds are those in which the double bond close to the nitrogen atom in the

  string has the configuration (E) trans.

  A particularly preferred compound is

  (E) -N- (3-chloro-7-benzolblthienylmethyl) -N-methyl-6,6-

  dimethyl-hept-2-ene-4-ynylamine.

  The following examples illustrate the present invention without in any way limiting its scope.

  all temperatures are in degrees Celsius.

Example 1

  N- (7-benzolblthienylmethyl) -N-methyl-6,6-dimethylhept-

  2-ene-4-ynylamine in the form (E) and (Z) Ecomposed la) and and lb) respectivelyl A mixture of 10.5 g of N- (7-benzolbl thienylmethyl) methylamine, 8.2 g of potassium carbonate and 100 ml of dimethylformamide,

  dropwise 12 g of 1-bromo-6,6-dimethyl-hept-2-

  ene-4-yne and shake overnight

  The reaction mixture is removed and the solvent is removed under reduced pressure. The evaporation residue is partitioned between ether and a saturated aqueous solution of sodium bicarbonate, the organic phase is dried, concentrated in a rotary evaporator, and the mixture is evaporated. the residue is chromatographed on silica gel (eluent:

  4/1 mixture of toluene and ethyl acetate).

  first holds the isomer (E) then the isomer (Z) in the form of oils The hydrochloride of the isomer (E)

at 148-158.

Example 2

  N- (3-chloro-7-benzolblthienylmethyl) -N-methyl-6,6-

  dimethyl-hept-2-en-4-ynylamine in the form (E) and (Z) lcomposed 2 a) and 2 b) respectivelyl

  To a mixture of 1.4 g of 7-bromomethyl-3-

  chloro-benzolblthiophene and 480 mg of sodium carbonate in 40 ml of dimethylformamide, 690 mg of N- (6,6-dimethyl-hept-2-en-4-ynyl) methylamine dissolved in dimethylformamide are added dropwise, and we

  stirred overnight The reaction mixture was concentrated

  The organic phase is washed with saturated aqueous sodium bicarbonate solution, dried and evaporated. silica (eluent: 95/5 mixture of toluene and ethyl acetate)

  the isomer (E) then the isomer (Z) in the form of oils.

  The hydrochloride of the isomer (E) melts at 180 ° -184 °.

  By proceeding in a manner analogous to that described in Examples 1 and 2, the compounds

  of the following formula I (R 1 = H, R 2 = CH 3).

  Example 1R R 4 R 5 Position of the Configuration, Data Example I j physicochemical side chain _ _ _ _ _ _ p__ _ __ _ _ _ _ _ _ _ _ _ J ortant R 3 _ _ _ _ _ _ _ _ _ 3 - C (CH) HH 3 E oil F 1

3) 3 1 60-1650

  b) Z oil 4 a) CH -C (CH 3) H H 3 E oil b) Z oil a) H H 7 E oil F 1

128-13 11

  b) Z oil 6 a) -C (, CH 3) 3 3 -Br H 7 E F = 51-57 o:

F 1) -168-1740

  b) Z oil 7 a) 4-Br H 7 EF = 55-58 o 8 a) 2-Cl H 7 EF 67-70 'b) Z oil 9 a) HH 4 E oil F 1' 182-187 o Z oil Example 1 R 3 R 4 R Cniua on Position Data _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Co 3 gra in 4 _ _ _ _ _ _ _ _ _ _ physicochemical side chain 1 carrying R 3

_ _ __ __ _ _ __ 4 __

i-C (CH 3) 3 3 -F H 7 E oil FU 1

O-170 O

  a) 3-Cl H 4 E fluent F 1 = b) Z oil 12 a) 3-CF 3 H 7 E oil Fi 3 1 75-18 ao b) Z oil 13 -C (CH 3) 3 2-FH 7 E oil F 1) 141-15 OC 14 -I H 4 E oil FU i 195-206 o and 7 EF = 10-1070 b) 3-COCH-3b S) z huiie 16 3 CH 3 H 7 E oil F 16 a) 3-CH 3 H 7 E 1 85-187 ob) Z oil 17 a) - C = CH 2 HH 7 E oil F 1, CH 2 134-143 o

CH -

  Example R 3 j R 'oiinde the 1 Cniuain Data 3 4 5 chaine physicochemical chalne bearing R 3 H

3 CH 20 H

3-CHO 2-Cl 3CN

2-SCH 13

2-SCH 3

3-CH = C (Br) 2 '

3-C = -CH

  z E E Z E E E E oil oil oil

F = 820

oil oil F) = 188-192 o, oiled

F = 45-5001

F1 oil

118-125 "

  oil 1) = Melting point of hydrochloride 17 b) a) b) 21 a) b) C Hc 2 CH 3

C (CH 3)

  Example 3 R 4 R 5 Position of the configuration Physicochemical side chain data I _________ I carrying R 3 26 -C (CH 3) 3 | 3-COOCH 3 H 7 E oil 27 3-CH-CH 2 H 7 E hui 1 e 28 "3-CH = CHCN H 7 E H e 1 29" 2-Br 3-CN 7 E oil 3CH 2 CN H 7 E oil 31 3-CH 20 CH 3 H 7 E oil 2 l NMR spectrum CDC 139 Stand ard TMS): a) E 7.7 (dd J7 2H zi, 1 1-1.1, 7,2-7, 54H); 6.16 (dt, 36 & 2 x 6.5 Hz, 1H); 5.66 (dtp J = 16 & 2 xl Hz, 1H); 3.74 2H); 3.10 (dd, J = 6.5 & 1 Hz, 2 M); 2 p 2 (s, 3H); 1.22: 7.7 (dd, J = 7Hz, 1H, 1H); 7.15-7.45 (m, 4H); 6.04 (dt, 3 = 11 & 2 x 7 HzIH), 5.6 (dt, J = 11 & 2 xli-iz, 1H); 3.78 (s, 2H) -, 3.34 (dd, J = 7Hz, 2H), 2.24 (s, 3H);

1.24 (s, 9 Fi).

  2 a) E 7.78 (dd, J = 7 & 2 Hz, 1H); 7.25-7.5 (m, 3H); 6.16 (dt, J = 16, 2 x 6-1, 1 M); 5.65 (dt, J = 16 & 22Hz, 1H), 3.76 (s, 2H); 3.10 (dd, J = 6 & 1 Hz, 2 P); 2.20 (s, 3H);

1.22 (s, 9H).

  b) Z 7978 (dd, J = 7 & 2 Hz, 1H), 7.2-7.5 (m, 3H); 6.05 (dt, J11 & 2 x 6.5 Hz, 1H); 5.63 (dt, J = 11 - 2 x 1 Hz, 1H); 3.8 H); 3.33 (dd, J = 6.5, 1Hz, JH); 2.24 (s, 3H); 1.24

(89.9 H).

  a) E 7.8-8.05 (m, 2H); 7 # 25-7.5 (m, 3H); 6.16 (dt, J 16 & 2 x 6.5 Hz, 1H); 5.66 (dt, J = 16 & 2 xl Hz, 1H); 3.7 (s, 2H); 3.1 (dd, 6.5 + 1Hz, 2H); 2.24 (s, 3H), 24 (s, 9H). b) z 7.8-8.0 (m, 2H), 7.2-7.5 (m, 3H); 6.0 (dt, J = 2, 5 Hz, 1H); 5.63 (t; t, J = 11 & 2 xli-iz, 1H); 3.72 (s, 2H); 3.3 (dd, J = 6.5Hz, 2H, 2.24 (s, 3H), 1.24 (s, 9H), 4a) E 7.8-8, 1 (m, 2H); 7.25-7.5 (m, 3H); 6.18 (dt, J = 16, 2x6.5Hz, 1H); 5.7 (dt, J = 16Hz, 1H); 3.72 (s, 2 M); 3.12 (dd, J = 6.5 & 1 Hz, 2H); 2.24 (s, 3H); 1.3-1.6

  (ps, 2H); 1.20 (s, 91-1); 1.0 (s, 3H).

  b) Z 7.8-8.1 (m, 2H); 7.2-7.5 (m, 3-14); 6.04 (dt, J = M 2 x 7 Hz, 1H); 5.67 (dt, J = 11 & 2 x 1 Hz, 1H); 3.78 (s, 2H); 3.35 (cld, 3-7 & 1, 2H); 2.3 (s 3H), 1.3-1 6 (p-uqu,

  2H); 1.22 (s, 9H) -, 1.02 (t, 3H).

  7.78 (dd, J = 7 & 2 Hz, 1H); 7.25-7.5 (m, 4H); 6.20 (dt, J = 16 & 2 x 6, 4Hz, 1H), 5.70 (dt, J = 16 & 2 x 1Hz, 1H);

  3.77 (s, 2H); 3.12 (dd, J = 6.4, 1Hz, 2H); 2.22 (s, 3H), -

  1.3-1.6 (m, 2H); 1.18 (s, 6H), 0.98 (spp, 3H).

  c) E d) Z 7.88 (dd, J = 6.5 & 2.5 Hz, 11-1); 7.2-7.5 (ni, 4H); 6.1 (dt, J = 11-20 Mz, 1H); 5.65 (dt, J = 11% 2 x 1 H-z, 11-1); 3.8 (i, 2H); 3.35 (dd, J = 7 & 1 Hz, 1H); 2.26 (s, 3H);

  1.3-1.7 (m, 2H), 1.2 (s, 6H); 1.0 (ps t, 3H).

  E 7.77 (dd, J 7 & 2 F Iz, 11-1); 7.2-7.55 (m, 3H); 6.18 (dt, J = 16, & 2 x 6.5 Hz, 1H); 5.66 (dt, J = 16 & 22Hz, 1H); 3.8 (s, 2H); 3, i (dd, J = 6.5 & 1 Hz, 2H); 2.22 (s, 3H);

1.24 (s, 9H).

  b) Z 7.88 (dd, J = 7: 2 Hz, 1H) -, 7.2-7.55 (m, 3H); 6.05 (dt, J = 11 & 2 x 6 Hz, 1H); 5.64 '(dt, J = 11 & 2 x 1 Hz, 1H); 3.8 (s, 2 F-1); 3.3 (dd, J = 6Hz, 2H); 2.24 (s, 3H); 1.24

(s, 9H).

  is 7 'a) E 7.25-7.6 (m, 4H); 7.22 (dt, J = 16 u 2 x 7 Hz, 1H); 6.70

  (dt, 3 = 16 u 2 x 1 Hz, 1H); 3.96 Cs, 2H); 3.17 (dd, J = 7, u.

  1 Hz, 2H); 2.25 Cs, 3H); 1.24 Cs, 9H).

  8 at 7.58 (dd, J = 7Hz, 1H); 7.1-7.4 (m, 3H); 6.20 (dt, J = 16 u 2, 5c, 7Hz, 1H); 65 (dt, J = 16Hz, 1H); 3.68 (s, 2H); 3.08 (dd, J = 7Hz, 2H); 2.20 Cs, 3M); 1.22 Cs, 9H). # 58 (dd, 3 v: 7 u 2 HZ, 1H); 7.1-7.4 (m, 31A); 6.88 (dt, J = 11, u x 7 Hz, 1H); 5.64 (dt, J = 11 u 2 x 1 Hz, 1H); 3.72 Cs, 2H); 3.34 (dd, J = 7Hz, 2H); 2.24 (s, 3H);

1.24 (9.9 H).

  7.5-7.85 (m, 2H); 7.2-7.45 (m, 3H); 6.12 (dt, J = 16 u.

  2 x 6.5 Hz, 1H) L 5.64 (dt, 3 = 16 u 2 x 1 Hz, 1 M); 3.76 Cs, 2H) J 3.10 (dd, J = 6.5HzHz, 2H); 2.18 Cs, 3H); 1.2 Cs, E b) Z 9 a) E

  b) 7.5-7.8 (m, 2H); 7.1-7.4 (m, 3Hi, 5.96 (dt, J = 11 u.

  2 x 6.5 Hz, 1H); 5.6 (d, J = 11 Hz, 1H); 3.78 Cs, 2H); 3.30

  (d, J = 6.5 Hz, 2H); 2.20 Cs, 3H); 1.24 Cs, 9H) -

  Io 'a) E 7.70 (dd, J = 75 Hz, 1H); 738 (t, 3 = 75 Hz, 1H); 7.28 (dd, J = 75 Hz, JH); 68 (d, 3 = 25 Hz, 1H);

  6.19 (dt, J = 16 u 2 x 6 5 Hz, 1H), 68 (dt, J = 16 u.

  2 xl 5 Hz, 1H), 376 Cs, 2H); 3 (dd, J = 6 5 u 1 5 Hz,

2H); 21 (s, 3H); 1 22 Cs, 9H).

25 - '

  11a) E 73 (dd, 3 = 75 Hz, 1H); 7 42 (dd, J = 75 u.

  2.0 Hz, 1H); 32 (t, J = 75 Hz, 1H); 31 (s, 1H); 6 12 (dt, 3 = 16 u 2 x 6 5 Hz, 1H); 65 (dt, 3 = 16 u2 x 5 Hz, 1H); 4 (s, 2H); 16 (ddI, J = 6.55 Hz, 3H-); 2 23 (s,

3H); 1 24 (s, 9H).

  b) Z 73 (ddI, J = 75 Hz, 1H); 42 (ddI, J = 75 u.

  2.0 Hz, 1H); 32 (t, J = 75 Hz, 1Hi); 7 32 (s, 1H); (DtJ = 11 u2 x 7 Hz, 1H); (Dt, J = 1 u 2 x 1 2 Hz, 1H); 19 (s, 2H); 42 (dd, 3 = 655 Hz, 2H-); 2 26 (s,

3H); 1 26 (s, 9 H).

  12a) E 790 (s, 1H); 86 (1H); 42 (t, J = 75 Hz, 1H); 7 25

  I 5 (1H); 16 (dt, 3 = 16 u2 x 65 Hz, 1H); 65 (d, 3 = 16 u.

  2 x 15 Hz, 1H); 78 (s, 2H); 3 (dd, J = 6 5 u 1 5 Hz,

  2H); 22 (s, 3H); 1 24 (s, 9H-).

  (b) Z 89 (s, 1H); 86 (1H); 42 (t, 2 x 75 Hz, 1H); 7 30

  (1H); 6 04 (dt, 3 = 11 u 2 x 7 Hz, 1H); 64 (dt, 3 = 11 u.

  2 x 12 Hz, 1H); 80 (s, 2H) i; 33 (dd, 3 = 6 5 u I 5 Hz,

2H); 24 (s, 3H); 1 24 (s, 9H).

  E 7 52 (dd, J = 75 Hz, 1H); 28 (t, 3 = 75 Hz, 1H) P; Δ 12 (dd J = 7.52 Hz, 1H); 69 (d, J = 30 Hz, 1H-);

  6.18 (dt, 3 = 16 u 2 x 6 5 Hz, 1 H; 68 (d L, 03 = 16 u.

  1.5 Hz, 1H); 68 (s, 2H); (D1 1, J = 6.55 Hz, 2H-);

2.21 (s, 3H); 23 (s, 9H-).

  E 63 (m, 1H); (D, J = 1 Hz, 1H); (M, 2H); 14 (dy J = 16 u 2 x 6 5 Hz, 1H); 66 (dt, J = 16 u 2 x 15 Hz, 1H); 68 (s, 2H); 308 (dd, J = 6.55 Hz, 2H); 2 (s,

3H); 1 24 rs, 9 H) -

  a) E 8.72 (dd, J = 75 Hz, 1H); (S, 1H); 45 (t, J: = 7.5 Fiz, 1H); 27 (m, 1H); 18 (dt, J = 16 u 2 x 65 Hz, 1H); 68 (dt, J = 16 u 2 x 1 5 Hz, 1H i, 3 78 (s, 2 H), 3 11 (dd, J = 6 5 u 1 5 Hz, 2 H); COCH 2 21 (s, 31-1);

1.24 (s, 9H).

  b) Z 8 72 (dd, J = 75 u 20 Hz, 1H); 830 (S, 1H); 746 (t, J = 75Hz, 1H); (M, 1H); 606 (dt, J = 11 u 2 x 7 Hz, JH); 66 (dt, J = 11Hz, 1H, 1H); 82 (s, 2H, 3 (d = J = 6, 5 1-1, 2H), 265 (s, COCH), 24 (s, 31-1);

- = - '' 3

1.25 (s, 9H).

  16 a) E 7.68 (dd, J = 75 Hz, 1H); 740 (t, J = 75 Hz, 1H); 7.30 (m, 1H); 7 (qua, J = 1 Hz, 1H); 6 (dt, J = 16 U. 2x6.5 Hz, 1H); 70 (dt, J = 16 u 2 x 1 5 Hz, 1 HJ, 3 7 to (s, 2 H), 3 12 (dd, J = 6 5 u 1 5 Hz, 21-i); J = 1 Hz,

  3H); 24 (s, 31-i); (S, 9H).

  b) Z 688 (dd, J = 75 Hz, 1H); 740 (t, J = 75 Hz, 1H);

  7.30 (mH); (Qua, P = 1 Hz, 1H); 6 09 (dt, J = 1 u.

* 2 x Fiz, 1H); 66 (dt, J = 11 u 2 x 1 2 Hz, 1 F-1); 381 (s, 2H); 36 (dd, J = 6.55 Hz, 21-i); 247 (d, 3 = 1 Hz,

3H); 28 (s, H); 1 27 (S '9 p) -

  7.75 (d 0, J = 75 Hz, 11-4); 2-7 (m, 4H); 6 (clt, J 16 U 2 x 6 5 Hz, 1H); 81% (d 4 t, 3 = 16 u 2 x 5 Hz, 11-1); 5.2-5 4 (m, 2H); 77 (s, 2H); 3 14 (dd, 3 = 65-1.5 Hz,

2H), 23 (s, 3H); 1 90 (m, 3H).

  17a) E b) Z '775 (m, 1H); 72-7 (m, 4H); 19 (dt, J = 11 u 2 x 7 Hz, 1H); 75 (dt, J = 11 u 2 x 5 Hz, 1H); 2-5 (M, 2H); 3.81 2H); 37 (dd, J = 6.55 Hz, 2H); 28 (s, 3H);

1.93 3H).

  E 80 (dd, J = 752 Hz, 1H); 37 (t, J = 75 Hz, 1H); 7.41 (s, 1H); (M, 1H); 18 (dt, J = 16 u 2 x 6 5 Hz, 1H); 68 (dt, J = 16 u 2 x 15 Hz, 1H); 95 (d, J = 1 Hz, 1H), 372 (2H); (Dd, Jr-6, 5 Hz, 2H); 2 23 (s,

3H); 1 24 9 H).

  19 E 10 17 (s, 1H); Δ -66 (dd, J = 75 Hz, 1H); 8 (s, 1H); 747 (t, J = 75 Hz, 1H); (M, 1H); 18 (dt, J = 16 u 2 x 65 Hz, 1H); 70 (dt, J = 16 u: 15 Hz, 1H); 80 (s, L-2H); 12 (dd, J = 6.55 Hz, 2H); 23 (s, 3H); 25 (s, 9H). E, 68 (dd, J = 75-1-1z, 1H); 7 (t, J = 75 Hz, 1H); 7.15-7 (rn, 1H); 6 (dt, J = 16 u 2 x 6 5 Hz, 1 H), 65 (dt, J = 16 u 2 x 15 Hz, 1H); 375 (s, 2H); 3 10 (dd, J = 6)

  U 1 5 Hz, 2 H); 2 (s, 3H); 22 (s, 9H).

  b) Z 768 (dd, J = 752 Hz, 1H); 7 (t, J = 75 Hz, 1H); 7.15-73 (m, 1H); 608 (dt, J = 11 u 2 x 6 5 Hz, 1H); 65 (dt, J = 11 u 2 x 15 Hz, 11-1); 78 (s, 2H), 34 (dd, J = 6)

  u 1 5 Hz, 2 H); 24 (s, 3H); 1 24 (s, 9H).

  8.18 (s, 1H); 95 (dd, J '7, 5 Hz, 1H); (T, J = 15 Hz, IHY, δ 25-7 4 (m, 1H), δ 2 (dt, J = 16 U. 2 × 6 5 Hz, JH), δ 70 (dt, J = 16); u 2 xl 5 Hz, 1H); 3 82 (s, 21-i) i 3 14 (dd, J = 6 5 u 1 5 Hz, 2 P); 22 (s, 31-i); s

9 H) 1

21 to) E

  b) Z 8 18 (s, 1H); 796 (dd, J = 751 Hz, 2H); 7 52 (t, 3 = 75 Hz, 1H), 6O8 (dt, J = 11 u 2 x 6 5 Hz, 11-1); 5 68 (dt,

  J = 11 u 2 x 5 Hz, 1H); 86 (s, 2H); J 36 (dd, J = 65 u.

  1.5 Hz, 2H); 26 (s, 3H); 1 26 (s, 9 H).

  E 62 (Ddy J = 752 Hz, 1H); (T, J = 75 Hz, 1H); 7.18 (dd, J = 752 Hz, 1H); 6 (dt, 3 = 16 u 2 x 6 5 Hz, 1H); 67 (dt, J = 16 u 2 x 15 Hz, 1H), 374 (s, 2H); (Dd, J = 6.55 Hz, 2H); 26 (s, 3H); 22 (s, 3H); 1 24

9 FI).

  E 7 55 (dd, J = 75 Hz, 1H); 26 (t, J = 75 Hz, 1H); 7.19 (s, 1H); 13 (dd, J = 752 Hz, 11-1); 16 (dt, J = 16 u 2 x 6 5 Hz, 1H); 67 (dt, J = 16 u 2 x 1 5 Hz, 1H) -, 699 (sir 21 O; 3 10 (dd, J = 561, 14 FD, 261 (s, 3H); ; 2 21

(9, 3H); 1, 24 (9, 91-4).

  24 E 8 1 (d 1 = 1 5 Hz, 1 H), 7 (d, J = 15 Hz, 1); 68 (dd, J = 752 Hz, 11-1), 74 (t, J = 75 Hz, 1H); 7 2-7 4 (m,

  H); 6 2 (dt, J = 16 u 2 x 6 5 Hz, 1H); 58 (dt, J = 16 u.

  2 xl 5 Hz, 1H); 78 (s, 2H); 3 (dd, J = 6 5 u 1 5 Hz,

21-0; 2 (s, 3H); 22 (s, 9H).

  E 79 (dd, J = 752 Hz, 1H); 74 (s, 1H); 74 (d, 3 = 75 Hz, 1H); 73 (dd, J = 75 Hz, 1H); 6 18 (dt,

  J = 16 u 2 x 6 5 Hz, 11-i); 68 (dts J = 16 u 2 x 15 Hz, 1H), -

  317 to (s, 2H); 3 (s, 1H) i 3 1 (dd, J = 755 Hz, 2H); 2.22 (s, 3H); 24 (s, 9H); 1 5

2520741-

  23. 26 E 8 55 '(dd, J = 752 Hz, 1H); 8 42 (s, 1H); 7.45 (t, J = 75 Hz, 1H); 7 3 <m, 1H); 6 18

  <dt, J = 16 u 2 x 6 5 Hz, 1H); 5 66 (dt, J-

  16 u 2 x 1 5 Hz, 1H); 95 (s, 3H); 78 (s, 2H); 3 1 (d Id, J =? 6 5 u -1 5 Hz, 2 H); 2 2 (s,

3H); 22 (s, 9H).

  E 7 86 (d Id, S = 75 u 2 Hz, 111); 2-7 (min, 3H); 7.02 <ddd, J 18, 12 u 1 Hz-, 1H); 6 2 (dt, J 16 u 2 x 6 5 Hz, 1H); (Dd, J = 18-1.5 Hz, 1H); 65 <dt, J = 16 u 2 x 15 Hz, 1H); 38 (dd, J = 12-1.5 Hz, 1H); 3 78 C s, 2H); 3 1 (dd, J

  6 5 u 1 5 Hz, 2 H); 22 (s, 311); 22 (s, 9H).

  E 7 84 (cdd, J = 7, 5a, 2Hz, 1H); 780 (s, 1H); 7.7 (d, J = 16 Hz, 1H); 45 (t, J = 75 Hz, 1H); 34 (m, 1H); 18 (dt, J = 16 ua 2 x 65 Hz, 1H); 5.94 (d, J = 16H); 68 (dt, J = 16 u 2 x 1 Hiz, 1H); 78 (s, 2H); 3 1 (dd, J = 65 Tl 5 Hz, 2H 1); 2.2 (s, 3Hi); 22 (s, 9H) 29 E 766 Cdd, J = 752 Hz, 1H); 42 (t, J 7, 5I, 1H); 24 (dd, J 7 ta 2 Hz, 1H); G 16 Cdt, J 16 2 x 6 5 Hz, 1H 1); 64 (dt ', J = 16 ua 2 x 15 Hz, 1 l'); 3.74 (s, 211); Dd 3, J = 6, 5a, 5Hz, 2H); 2 2

(s, 311); 22 (s, 9H).

  E 644 (dd, J = 752 Hz, 1H); 7 (s, 1H); 7 42

  (t, J = 75 Hz, 1H); 32 (m, 1H); 6 2 (dt, J = 16 u.

  2 x 6 5 Hz, 1H); 68 (dt, J = 16 u 2 x 15 Hz, 1H); 3.9 (d, J = 1 Hz, 2H); 78 (s, 2H); 31 (dd, J = 65 Hz, 2H); 2 (s, 3H); 1 22 (s, 3H).

  E 7 8 (dd, J = 7.52 Hz, 1H); 7 (s, 1H); 7 4

  (t, J = 75 Hz, 1H); 7 3 (m, 1H); 6 2 (dt, J = 16 u.

  2 x 6 5 Hz, 1H); 7 (dt, J = 16 u 2 x 1 5 Hz, 1)); 4.72 (d, J = 1 Hz, 2H); 78 (s, 2H); 42 (s, 311); 3.1 (dd, J = 65 Hz, u 15 Hz, 2 H 1); 22 (s, 311);

(S, 9H).

  The products required for the preparation of the compounds of the formula I can be prepared, for example, as follows: A) 7-bromomethylbenzoleththio Ehene 6 g at reflux 7 g

  of 7-methylbenzolblthiophene, 8.5 g of Nbromosuccin-

  imide and a spatula tip of a, a'-azoisobutyro-

  nitrile in 50 ml of carbon tetrachloride.

  The resulting mixture is cooled, filtered and evaporated.

  raw can be used directly for the next step.

  After isolation, it melts at 57 (recrystalliza-

in isopropanol).

  The following compounds can be prepared

in a similar way.

  3-bromo-7-bromomethylbenzolblthiophene, 4-bromo-7bromomethylbenzolblthiophene, 7-bromomethyl-2-chlorobenzolblthiophene, 7-bromomethyl-3-chlorobenzolblthiophene, F = 75-79 (in ethanol), 7-bromomethyl 3-fluorobenzolblthiophene, oil, 4-bromomethyl-3chlorobenzolblthiophene, 7-bromomethyl-3-trifluoromethylbenzolblthiophene, 7-bromomethyl-2fluorobenzolblthiophene, 4-bromomethyl-2-chlorobenzolblthiophene, 3-acetyl-7-bromomethyllothiophene, 7-bromomethyl-3cyanobenzolblthiophene, 7-bromomethyl-2,3-dichlorobenzolblthiophene, 7-bromomethyl-3- (2,2-dibromovinyl) benzolblthiophene, 3-ethynyl-7bromomethylbenzolblthiophene, 7-bromomethyl-3-methoxycarbonylbenzolblthiophene, 7-bromomethyl- 3- (2-cyanovinyl) -benzolblthiophene, 2-bromo-7-bromomethyl-3-cyano-benzol-1-thiophene, 7-bromomethyl-3-cyanomethyl-benzol-1-thiophene and

  7-bromomethyl-3-methoxymethyl benzolphosphine.

  Each of these compounds can be used directly

for the next step.

  B) N-: 7 S: enzolblthienylmethylmethylamine To 40 ml of a 33% solution of methylamine in ethanol, the 7-bromomethylbenzolbl thiophene dissolved in dichloromethane is added and the mixture is allowed to stand overnight. concentration of the resulting mixture, the residue is taken up in

  dichloromethane and extracted with hydrochloric acid

  2 N water The aqueous phase is made strongly alkaline

  The organic phase is dried over sodium hydroxide and stirred with dichloromethane. The organic phase is dried over potassium carbonate, evaporated and distilled.

  the residue under reduced pressure, which gives the

  put-the title in the form of an oil E = 103 / 1.3 mbar.

  The following compounds can be prepared analogously: N- (3-chloro-7-benzolylthienylmethyl) methylamine,

  E = 130-132 / 1.3 Pascal, F (hydrochloride) = 250-255.

  N- (3-benzolblthienylmethyl) methylamine, E = 90-94 / 1.3 Pascal. N- (3cyano-7-benzolblthienylmethyl) methylamine:

hydrochloride melts at 280-285.

  N- (6,6-dimethyl-hept-2-en-4-ynyl) methylamine (mixture

  isomers Z, E): the product is obtained after chroma-

  silica gel graphite (eluent = 4/1 mixture of toluene and ethyl acetate) NMR spectrum: 5.3-6.3 (m, 2H); 3.4 (d, J = 6H) + 3.16 (d, J = 6Hz), 2H1; 2.38

  (s, 3H); 1.46 (s, 1H); 1.21 (s, 9H).

  N- (3-bromo-7-benzolblthienylmethyl) methylamine:

hydrochloride melts at 260-262.

  C) 3-bromo-7-methylbenzoleththioheene 25 g of methylbenzolblithiophene are dissolved

  in chloroform and added at room temperature

  After 1 hour, the mixture is poured into water, the organic phase is separated off, washed, dried and concentrated under reduced pressure. The title compound, contaminated with about 10% of 4-bromo-7-methylbenzothiothiophene is obtained as an oil after

  distillation under reduced pressure at 92-98 / 2.6 mbar.

  D) 2-chloro-7-m: thylbenzolblthioehene To a solution of 2 g of 7-methylbenzoththiophene in anhydrous ether cooled to -10, 8.4 ml of a 1.6 M solution of butyllithium is added dropwise. in hexane and shake the

  reaction mixture for one hour between 0 and -5.

  At a temperature of -30, 1 g of chlorine gas is added and, after removing the cooling bath, the mixture is heated to room temperature.

  about an hour, the mixture is washed several times

  taken with water, dried and concentrated in a rotary evaporator The title compound as well as

  obtained is used directly for the following reaction.

  boasts. The following compounds can be prepared analogously: 2-bromo-3-cyano-7-methyl-benzol-1-thiophene NMR spectrum: 7.76 (dd, J = 7.5 and 2 Hz, 1H); 7.46 (t, J = 7.5 Hz, 1H); 7.26 (dd, J = 7.5 and 2 Hz, 1H);

2.54 (s, z H).

  2-chloro-4-methyl-benzolblthiophène. E) 2,3-dichloro-7-methylbenzoththiothene 20 g of 7-methylbenzothiophthiophene are dissolved in carbon tetrachloride and saturated at room temperature with chlorine gas. After 2 hours the excess chlorine is removed. concentrate the mixture in a rotary evaporator and take the

  residue in dichloromethane The organic phase is washed

  with a saturated aqueous solution of bicarbonate

  of sodium, it is dried and evaporated in a

  rotary porator The title compound is obtained after

  crystallisation in methanol, in the form of

colorless rates melting at 48-50.

  2,3-dichloro-4-methylbenzolblthiophene

  can be prepared in a similar way.

  F) 3-Chloro-7-methylbenzol-1-thioheene 10 g of 2,3-dichloro-7-methylbenzo-1-thiophene are dissolved in 200 ml of ether and 28.8 ml of a 1.6 M solution of butyllithium is added dropwise. After 1 hour, the mixture is poured into a dilute aqueous solution of hydrochloric acid, the organic phase is separated off, washed and dried.

  and evaporated in a rotary evaporator.

  of the title thus obtained in the raw state is used directly for the next reaction (E = 60-62 / 0.13 Pascal). 3-chloro-4-methylbenzolblthiophene can

  be prepared in a similar way.

  G) 3-fluoro-7: Z-methylbenzolthothiohene

  To a solution of 18.1 g of 3-bromo-7-methyl-

  benzolblthiophene in anhydrous ether cooled to -78, is added dropwise 50 ml of a 1.6 M solution of butyllithium in anhydrous ether After 20 minutes, is introduced under an inert gas atmosphere and stirring, 9 g of perchloryl fluoride,

  while maintaining the temperature of the reaction mixture

  The resulting mixture was stirred for 30 minutes at -78, warmed slowly to 0, mixed with water, the organic phase separated, washed, dried and dried. concentrated under reduced pressure The residue is chromatographed on silica gel using hexane as eluent,

  which gives the title compound as an oil.

  H) -7-Methyl-3-trifluoromethyl benzol-2-thiothene A mixture of 2 g of

  3-bromo-7-methylbenzolblthiophene, 4.8 g

  Sodium fluoroacetate, 3 g of Cu I and 20 ml of methylpyrrolidone and heated to 1600 After a short time there is a gaseous evolution Agitation is continued for one hour at 1600 and then for another hour at 180 minutes. cooled the reaction mixture, poured into water, extracted with a mixture of equal parts of ether and hexane,

  washing the organic phase, drying it and concentrating it

  The crude product is chromatographed on silica gel using n-hexane as eluent. The title compound is thus obtained in the form of a colorless oil. 1) 2-Fluoro-7-methylbenzolblithiophene To a solution of 7 g of 7-methylbenzothiophene in anhydrous tetrahydrofuran is added dropwise to -78 ml of a 1.6 M solution of n-butyllithium in hexane After 20 minutes, 5.5 g of perchloryl fluoride are introduced while keeping the temperature below

  -60 After 30 minutes at -78, we let go up

  The temperature is mixed with water, the organic phase is separated off, washed and dried.

  and concentrated under reduced pressure.

  The residue is then suspended on silica gel using hexane as eluent.

title in the form of an oil.

  J): a: methyl-7-methylbenzolbthioehene

  At a melange of 2 g of 7-methylbenzolblithio-

  and 1.4 ml of acetic anhydride, 420 mg of boron trifluoride etherate are added and the mixture is heated at 60 for 80 minutes. The resulting mixture is poured onto ice, extracted with ether, the organic phase is washed, dried and

  it is concentrated in a rotary evaporator

  The residue is then chromatographed on silica gel using n-hexane as eluent. The title compound, contaminated with the 2-acetyl isomer, is thus obtained in the form of an oil which can be used directly for

next reaction.

  K) N- (3-methyl-7-benzolblthienylmethyl) methylamine

  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

  a) N- (tert-butoxycarbonyl) -N- (3-cyano-7-benzolblthienyl)

  methyl) methylamine 3.6 g of N- (3-cyano-7-benzolylthienylmethyl) methylamine and 3.9 g of ditert-butyl di-carbonate in dichloromethane are stirred for one hour at room temperature. solution under reduced pressure to give the title compound which is used directly for the next reaction Rf = 0.9

  (95/5 mixture of chloroform and ethanol).

  NMR Spectrum: 8.15 (s, 1H); 7.9 (d, 1H); 7.2-7.7 (m, 2H);

  4.75 (s, 2H); 2.8 (s, 3H); 1.5 (s, 9H).

  b) N- (tert-butoxycarbonyl) -N- (3-formyl-7-benzolylthienylmethyl) methylamine

  1.44 g of N- (tert-butoxycarbonyl) -

  N- {3-cyano-7-benzolblthienylmethyl) methylamine in anhydrous ether and to a solution of 1.2 M of diisobutylaluminum hydride in toluene is added dropwise to 0 ml. one hour at room temperature and the mixture is poured into ice cold 2 N acetic acid. Extracted with ether, the organic phase is washed to neutrality, dried and concentrated under reduced pressure. reduced pressure The title compound thus obtained in the form of an oil is used directly for the

next reaction.

  NMR spectrum: 10.1 (s, 1H, CHO); 8.6 (dd, 1H); 8.35 (s, 1H); 7.2-7.7 (m, 2H); 4.8 (s, 2H); 2.8 (s, 3H); 1.55 (s, 9H); 3-Formyl-7-methylbenzolblthiophene (F =

  55-60) can be prepared analogously.

  NMR spectrum: 10.0 (s, 1H); 8.4 (d, 1H); 8.2 (s, 1H);

7.1-7.7 (m, 2H); 2.55 (s, 3H).

  c) N- (tert-butoxycarbonyl) -N- (3-methyl-7-benzolylthienylmethyl) methylamine 5.1 g of N- (tert-butoxycarbonyl) -N- (3-formyl) -7- are heated for 10 minutes to 160 g. -benzolbl

  thienylmethyl) methylamine and 12 ml of hydrate hydrate

  85% zine in 40 ml of diethylglycol,

  said, 3.17 g of powdered potassium hydroxide

  The mixture is heated for one hour at 170 ° C.

  After cooling the reaction mixture, poured onto ice, extracted with ether, the organic phase washed, dried and concentrated under reduced pressure to give the title compound

  that is used directly for the next reaction.

  NMR spectrum: 7.2-7-8 (m, 4H); 4.7 (s, 2H); 28 (s, 3H); 2.4 (s, 3H);

1.5 (s, 9H).

  d) N- (3-methyl-7-benzolylthienylmethyl) methylamine The mixture is stirred for 30 minutes at 0.degree.

  N- (tert-butoxycarbonyl) -N- (3-methyl-7-benzol) thienyl

  methyl) methylamine in 15 ml of trifluoroacetic acid

  The mixture is then poured into ice, basified with sodium hydroxide, extracted with ether, the organic phase is washed, dried and concentrated under reduced pressure. the title compound: Rf = 0.15 (95/5 mixture of chloroform and ethanol) The compound can be

  used directly for the next reaction.

  N- (3-vinyl-7-benzolylthienylmethyl) methylamine (oil) can be prepared in a similar manner,

  N- (3-hydroxymethyl-7-benzolblthienylmethyl) methyl-

  amine (oil) and N- (3-formyl-7-benzolblthienylmethyl) methylamine (oil). L) 1-Bromo-6-methyl-2,6-heptadien-4-yne: 32. a) 6-methyl-1,6-heptadien-4-yne-3 10 g of isopropenylacetylene are taken up in anhydrous tetrahydrofuran and, under an inert gas atmosphere and at -20, 94.5 ml of a 1.6M solution of n-butyllithium are added dropwise to the solution. hexane. The mixture is then cooled to -78 and 8.5 g of acrolein are added dropwise. The reaction mixture is heated to room temperature, poured into a saturated aqueous solution of ammonium chloride and extracted at room temperature. several times with ether The organic phase is washed, dried and concentrated under reduced pressure.

an oil.

  NMR spectrum: 6.02 (ddd, J = 17, 10 & 5.5 Hz, 1H); 5.0 (m, 1H); 5.2-5.55 (m, 2H); 1.9 (dd, J = 1.4

& 1 Hz, 3 H).

  b) 1-bromo-6-methyl-2; 6-heptadiene-4-yne To 40 ml fuming hydrobromic acid, add

  dropwise an alcoholic solution of 6-methyl-

  1,6-heptadiene-4-yn-3-ol and the mixture is stirred for one and a half hours at room temperature. The mixture is then poured into ice and extracted with

  hexane The organic phase is washed several times

  taken with an aqueous solution of sodium chloride,

  it is dried and concentrated in a rotary evaporator

  According to the NMR spectrum, the oily product consists

  to a 3: 1 mixture of (E) and (Z) -1-bromo-6-methyl-

  2,6-heptadiene-4-yne that can be used directly

for the next reaction.

  NMR spectrum (pure E isomer): 6.28 (dt, J = 15.5 & 2 x 7 Hz, 1H); 5.85 (d, J = 15.5 Hz, 1 tl); 4.0 (dd, J = 7 & 0.7 Hz, 2H); 5.2-5.4 (m, 2H);

1.90 (dd, J = 1 & 1.4 Hz, 1H).

  M) N-Butylcarbyl-N-3-hydroxybenzo-1-methyl-1-methyl-methylamines 100 mg Na BH 4 are reacted with 600 mg of

  N- (tert-butoxycarbonyl) -N- (3-formyl-7-ben'zolblthienyl)

  methyl) methylamine dissolved in ethanol and stirred for 2 hours at room temperature The reaction mixture is concentrated, the residue is partitioned between ether and water, the organic phase is washed,

  Dry and concentrated in a rotary evaporator.

  The oily product thus obtained is used directly

  for the next reaction 3-hydroxymethyl-7-methyl-

  benzolblthiophene can be prepared analogously.

  2 h 3-bromo-7-methylbenzothiothiophene and 3 l of CuCn in anhydrous pyridine were dissolved

  and heated for 12 hours at 220 in an autoclave.

  Cool the mixture, concentrate it and disperse

  the residue between dichloromethane and chlorinated

  dilute water The organic phase is washed, dried and concentrated After chromatography of the residue on silica gel (eluent: toluene) the compound of

  title as pale yellow crystals melting at 82-84.

  O) N-: 2 m: ethylthio-3-bromo-7-benzol-1-thienylmethyl 11 To a solution of 2.55 g of N- (3-bromo-7-benzo-1-thienylmethyl) -methylamine in anhydrous ether is added dropwise, under an inert gas atmosphere and 70, 13.8 ml (2 equivalents) of a 15% solution of n-butyllithium in hexane A minus -70, 1.9 ml of dimethyl disulfide and

  gradually heat the reaction mixture to

  The mixture is then poured into 2N hydrochloric acid cooled by ice,

252 0741

  After stirring, the acid phase is separated, basified with sodium hydroxide and extracted with ether. The ethereal phase is dried and concentrated under reduced pressure to give the title compound. form of an oil The product can be

  used directly for the next reaction.

  NMR spectrum: 7.2-7.7 (m, 3H); 4.0 (s, 2H); 2.6

  (s, 3H); 2.45 (s, 3H); 1.5 (broad, N-H).

  P) N- (2-methylthio-7-benzol) thienylmethyl-methyl

amine

  To a solution of 0.3 g of N- (2-methylthio)

  3-bromo-7-benzolblthienylmethyl) methylamine in

  the anhydrous ether is added dropwise under

  mosphere of inert gas and at -70, 1.4 ml of a solution

  15% n-butyllithium in hexane and stirring is continued for half an hour at -70 ° C. The mixture is then poured into ice-cold 2 N hydrochloric acid, stirred, separated, and filtered. The acid phase is basified with sodium hydroxide and extracted with ether. The ethereal phase is dried and concentrated under reduced pressure to give the title compound as a solution. oil The compound can be used directly for

the next reaction.

  Q) 3: 2,2-dibromovinl: -: 7-methylbenzolblthiophene

  To 1.04 grams of zinc powder and 4.17 grams of

  phenylphosphine in dichloromethane, 5.27 g of tetrabromomethane dissolved in dichloromethane are added dropwise under an inert gas atmosphere and under cooling. After stirring for 24 hours at room temperature, the mixture is added dropwise at room temperature.

  drop, under cooling, 1.4 g of 3-formyl-7-

  methylbenzolblthiophene dissolved in dichloromethane

  thane and stir overnight at room temperature. Then pentane and

  the precipitated (C 6 H 5) 3 PO was filtered off.

  The filtrate is evaporated under reduced pressure and the residue is chromatographed on silica gel, which

  gives the title compound, F = 75-78.

  R) 3-E: methyl-7-methyl benzo Elblthioph L

  To a solution of 0.6 g of 3- (dibromovinyl)

  7-methylbenzolblthiophene in anhydrous tetrahydrofuran is added dropwise, under an inert gas atmosphere and at -78, 3.38 ml of a 15% solution of n-butyllithium in hexane. The mixture is then poured for one hour at -78 and warmed to room temperature. The mixture is then poured into a saturated aqueous solution of sodium bicarbonate and extracted with ether. The ethereal phase is washed, dried and the concentrate, which gives the title compound The compound can be used

  directly for the next reaction.

  NMR spectrum: 7.85 (dd, J = 7 & 2 Hz, 1H); 7.70 (s, 1H); 7.40 (t, J = 7 Hz, 1H); 7.20 (dd, J = 7 & 2 Hz,

1H); 3.28 (s, 1H); 2.58 (s, 3H).

  S) N: -2 tr 21 h: u N 2 Lyc 1 rb 2 nlyl: I :: Z-binyl: 7-benzolylbenzylimethylamine: Methylamine A suspension of 0.43 9 methyltriphenylphosphonium bromide in tetrahydrofuran anhydrous is added dropwise under a

  inert gas, 0.7 ml of a 15% solution of n-butyl-

  lithium in hexane and the mixture is stirred for one hour at room temperature.

  dropwise a solution of 0.37 g of N- (tert-

  butoxycarbonyl) -N- (3-formyl-7-benzolbithienylmethyl) methylamine

  in tetrahydrofuran and the resulting mixture is heated to

  flow for 20 hours The reaction mixture is then poured onto ice, extracted several times with ether, the organic phase is washed, dried and evaporated after chromatography on silica gel (eluent 9: 1 mixture of toluene and glacial acetic acid), the compound is obtained.

title in the form of an oil.

  NMR spectrum: -7.88 (dd, J = 7.5 & 2 Hz, 11); (S, 111); 7.44 (t, J = 7.5 Hz, 1H); 7.25 (dd, J = 75 & 1 Hz, 1H); 7.02 (ddd, J = 18.12 & 1 Hz, 1H); 82 (dd, J = 18 & -1.5 Hz, 1H); 5.4 (dd, J = 12 & 1.5Hz, 1H); 4.72 (s, 211); 2.8 (s, 31 I);

1.5 (s, 9H).

  3- (2-cyanovinyl) -7-methyl-benzo-L-thiophene

  can be prepared in a similar way.

  NMR spectra: 7.80 (s, 11); 7.76 (dd, J = 7.5 & 2Hz, 1 L); 7.68 (d, J = 16Hz, 1H); 7.46 (t, J = 7.5 Hz, 1H); 7.26

  (m, 1H); 5.96 (d, J = 16 Hz, 1H); 2.6 (s, 31H).

  T) 3 yanomethyl: -7: ethyl-benzolblthioehene

  290 mg of 3-hydroxymethyl-7-methyl-

  benzolblithiophene in ether, 0.6 ml of SO C 12 are added and the mixture is stirred for 2 hours at room temperature.

  ice, the organic phase is washed to neutral

  it is dried and evaporated under reduced pressure.

  3-Chloromethyl-7 is dissolved in acetone.

  methyl-benzolblthiophene thus obtained in the crude state, mixed with an aqueous solution of 170 mg of KCN and refluxed for 18 hours The reaction mixture is concentrated, the residue is partitioned between water and ether The organic phase is washed, dried and evaporated. After chromatography on silica gel (eluent: toluene), the title compound is obtained.

title in the form of an oil.

  NMR spectrum: 6.7-7.6 (m, 4H); 3.6 (broad, 2H); 2.5 (s, 3H).

  U) 3-Methoxymethyl-7-methyl-benzolblthene hene x

  40 mg of 3-hydroxymethyl-7-methyl-

  benzolblthiophene in tetrahydrofuran, mixed with 82 mg of 80% NaH, and after addition of 48 mg of methyl iodide, the mixture is heated for half an hour at 50 ° C. Extracted several times, the organic phase is washed, dried and concentrated in a rotary evaporator. The residue is chromatographed on silica gel (eluent: 95: 5 mixture of toluene and glacial acetic acid). give the

  composed of the title in the form of an oil.

  NMR spectrum: 7.2-7.9 (m, 4H); 4.75 (s, 2H); 3.5 (s, 3H);

2.66 (s, 3H).

Claims (1)

The (N-alkyl-N-allylamino-alkyl) benzothiophenes in which the allyl-amino-alkyl side chain is located at the 2, 3, 4, 5, 6 or 7 position of the benzothiophene ring, the side chain comprising a tert-alkyl-ethynyl or alkenyl-ethynyl group as end group when it is in the 2 or 3 position. 2. The benzothiophene derivatives having the formula ICHCH 2 CH CH CCR 3 in which R 1 represents hydrogen or methyl, R 2 is methyl or ethyl, R 3 is tertiary alkyl or alkenyl, and R 4 and R 5 are each independently hydrogen. , halogen, hydroxy, lower alkynyl, cyano, formyl, lower alkoxy, lower alkylcarbonyl, lower alkoxycarbonyl, lower alkyl optionally bearing one or more substituents selected from halogens and cyano, hydroxy, alkylthio inf. laughing and lower alkoxy, or lower alkenyl group having one or Sev- eral substituents selected from halogen and cyano, in free base form or in the form of a salt of acid addition. 3. The benzothiophene derivatives of formula I according to claim 2, characterized in that the chalky allylaminoalkyl is located in position 4 or 7 of the benzothiophene ring. 4. The benzothiophene derivatives of formula I according to claim 2 or 3, characterized in that R 4 and / or R 5 are located at the 2-position and / or 3-position of the benzothiophene ring. 5. Benzothiophene derivatives of formula I according to any one of claims 2 to 4, characterized in that R 5 represents hydrogen and R 4 represents hydrogen, a halogen or a hydroxy group, lower alkyl or lower alkoxy . 6. (E) -N- (3-Chloro-7-benzolblthienylmethyl) -N-methyl-6,6-dimethyl-hept-2-en-4-ynylamine, as free base or as a acid addition salt. A process for the preparation of the benzothiophene derivatives specified in claim 2, in free base form or in the form of an acid addition salt, characterized in that a) a compound of formula II, R is reacted Wherein R 1, R 2, R 4 and R 5 'have the meanings given in claim 2, with a compound of formula III A-CH 2 -CH = CH-CC-R 3 <III ) in which R 3 has the meaning given in claim 2 and A signifies a group capable of being eliminated, or b) reacting a compound of formula IV R 4 CH-A () R 5 S wherein R 1, R 4 and R 5 have the meanings given in claim 2 and A signifies a group capable of being eliminated, with a compound of formula YR 2 () HN CH 2 CH = CH CCR 3 in which R 2 and R 3 have the meanings given in claim 2, and the compounds thus obtained are recovered in form 8. The use of the benzothiopene derivatives specified in any of claims 1 to 6, in free base form or in the form of a chemically acceptable acid addition salt, as chemotherapeutic agents. 9. The use of the benzothiopene derivatives specified in any one of the claims   1 to 6, in free base form or in the form of an acid addition salt which is acceptable from the point of view of   chemotherapeutic agents, as anti-mycotic agents.   10. A medicine, characterized in that   contains, as active ingredient, a benzothio derivative   as specified in any of the claims   cations 1 to 6, in free base form or in the form of a pharmaceutically acceptable acid addition salt. chemotherapeutic view.   11. A pharmaceutical composition, characterized   in that it contains a benzothio derivative   as specified in any of the claims   cations 1 to 6, in free base form or in the form of a chemically acceptable acid addition salt, in combination with chemotherapeutically acceptable diluents or carriers.